Operator Versus Core Lab Adjudication of Reperfusion After Endovascular Treatment of Acute Ischemic Stroke.
Background and Purpose- The modified Treatment In Cerebral Ischemia (mTICI) score is the standard method to quantify the degree of reperfusion after endovascular treatment in acute ischemic stroke. In clinical practice, it is commonly assessed by local operators after the procedure. In clinical trials and registries, mTICI is evaluated by an imaging core lab. The aim of this study was to compare operator mTICI with core lab mTICI scores in patients included in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry. Methods- All patients with an intracranial carotid or middle cerebral artery occlusion with anteroposterior and lateral digital subtraction angiography runs were included. Operators determined the mTICI score immediately after endovascular treatment. Core lab neuroradiologists were blinded to clinical characteristics and assessed mTICI scores based on pre- and postintervention digital subtraction angiography. The agreement between operator and core lab mTICI scores and their value in the prediction of outcome (score on modified Rankin Scale at 90 days) was determined. Results- In total, 1130 patients were included. The proportion of agreement between operator and core lab mTICI score was 56% (95% CI, 54%-59%). In 33% (95% CI, 31%-36%), mTICI was overestimated by operators. Operators reported a higher rate of successful reperfusion than the core lab (77% versus 67%; difference 10% [95% CI, 6%-14%]; P<0.001). In 252 (33%) of 763 patients scored as incomplete reperfusion by the core lab (mTICI <3), the local read was mTICI 3. Multivariable logistic regression models containing either core lab scored or operator scored successful reperfusion predicted outcome on the full (C statistic of both models: 0.76) or dichotomized modified Rankin Scale (modified Rankin Scale, 0-2; C statistic of both models: 0.83) equally well. Conclusions- Operators tend to overestimate the degree of reperfusion compared with the core lab although this does not affect the accuracy of outcome prediction.


beta-NGF-endopeptidase: structure and activity of a kallikrein encoded by the gene mGK-22.
Mouse nerve growth factor (NGF) is cleaved at a histidine-methionine bond to release an NH2-terminal octapeptide (NGF1-8). The enzyme responsible, beta-NGF-endopeptidase, is structurally and functionally similar to gamma-NGF and epidermal growth factor-binding protein (EGF-BP) and cleaves mouse low molecular weight kininogen to produce bradykinin-like activity. These data have suggested that, like gamma-NGF and EGF-BP, beta-NGF-endopeptidase is a mouse glandular kallikrein. Evidence for a physiological role for NGF1-8 encouraged studies to further characterize the structure and function of this enzyme. Purified beta-NGF-endopeptidase migrated as a single band on isoelectric focusing and reducing SDS-polyacrylamide gels. As was expected, it removed NGF1-8 from NGF. Interestingly, enzymatic activity on an artificial substrate, and on NGF, was inhibited by NGF1-8 and by bradykinin. These studies further supported the view that beta-NGF-endopeptidase acts on both NGF and kininogen. The first 30 NH2-terminal amino acids of beta-NGF-endopeptidase were sequenced. This analysis demonstrated that the enzyme is encoded by the gene designated mGK-22 (Evans et al., 1987). The sequence of this gene corresponds to that of EGF-BP type A (Anundi et al., 1982; Drinkwater et al., 1987), and so studies were performed to determine whether or not beta-NGF-endopeptidase participates in EGF complex formation. Chromatographic and kinetic data gave no evidence that beta-NGF-endopeptidase is an EGF-binding protein. Our studies suggest that contamination of high molecular weight (HMW) EGF preparations with beta-NGF-endopeptidase erroneously led to earlier designation of the product of mGK-22 as an EGF-BP.(ABSTRACT TRUNCATED AT 250 WORDS)


Growth, collapse, and self-organized criticality in complex networks.
Network growth is ubiquitous in nature (e.g., biological networks) and technological systems (e.g., modern infrastructures). To understand how certain dynamical behaviors can or cannot persist as the underlying network grows is a problem of increasing importance in complex dynamical systems as well as sustainability science and engineering. We address the question of whether a complex network of nonlinear oscillators can maintain its synchronization stability as it expands. We find that a large scale avalanche over the entire network can be triggered in the sense that the individual nodal dynamics diverges from the synchronous state in a cascading manner within a relatively short time period. In particular, after an initial stage of linear growth, the network typically evolves into a critical state where the addition of a single new node can cause a group of nodes to lose synchronization, leading to synchronization collapse for the entire network. A statistical analysis reveals that the collapse size is approximately algebraically distributed, indicating the emergence of self-organized criticality. We demonstrate the generality of the phenomenon of synchronization collapse using a variety of complex network models, and uncover the underlying dynamical mechanism through an eigenvector analysis.


The application of qualitative research findings to oncology nursing practice.
The Oncology Nursing Society (ONS) has established an ambitious research agenda and professional priorities based on a survey by LoBiondo-Wood et al. (2014). With the overall goal to "improve cancer care and the lives of individuals with cancer" (Moore & Badger, 2014, p. 93) through research activities, translating those research findings to direct clinical practice can be overwhelming. As clinicians, understanding how to critique research for quality prior to incorporating research findings into practice is important. The ultimate goal in this critique is to ensure that decisions made about patient care are based on strong evidence. However, the process for appraisal of qualitative research can be ambiguous and often contradictory as a result of the elusive aspect of quality in qualitative research methods (Seale, 1999). In addition, with more than 100 tools available to evaluate qualitative research studies (Higgins & Green, 2011), a lack of consensus exists on how to critically appraise research findings.


Diabetes, driving, and the general practitioner.
The medical fitness of drivers who have diabetes is assessed primarily by general practitioners. A survey was made of the knowledge of driving and diabetes of 105 general practitioners in Glasgow. Ninety four (90%) knew that people who were insulin dependent were required by law to declare their condition to the Driver and Vehicle Licensing Centre in Swansea, but most were unaware that people with diabetes should not hold a "till 70" driving licence. Seventy one doctors (69%) claimed that patients were recalled individually for fitness to drive. The minimum visual acuity for driving was stated correctly by 37 (35%). Only eight respondents knew that a hypoglycaemic diabetic driver can be charged with driving under the influence of a drug (Road Traffic Act 1972), and the practical advice that was given to patients about hypoglycaemia and driving was unsatisfactory. As a group the general practitioners showed deficiencies in knowledge regarding diabetes and driving, suggesting a need for further postgraduate education.


A lightweight distributed framework for computational offloading in mobile cloud computing.
The latest developments in mobile computing technology have enabled intensive applications on the modern Smartphones. However, such applications are still constrained by limitations in processing potentials, storage capacity and battery lifetime of the Smart Mobile Devices (SMDs). Therefore, Mobile Cloud Computing (MCC) leverages the application processing services of computational clouds for mitigating resources limitations in SMDs. Currently, a number of computational offloading frameworks are proposed for MCC wherein the intensive components of the application are outsourced to computational clouds. Nevertheless, such frameworks focus on runtime partitioning of the application for computational offloading, which is time consuming and resources intensive. The resource constraint nature of SMDs require lightweight procedures for leveraging computational clouds. Therefore, this paper presents a lightweight framework which focuses on minimizing additional resources utilization in computational offloading for MCC. The framework employs features of centralized monitoring, high availability and on demand access services of computational clouds for computational offloading. As a result, the turnaround time and execution cost of the application are reduced. The framework is evaluated by testing prototype application in the real MCC environment. The lightweight nature of the proposed framework is validated by employing computational offloading for the proposed framework and the latest existing frameworks. Analysis shows that by employing the proposed framework for computational offloading, the size of data transmission is reduced by 91%, energy consumption cost is minimized by 81% and turnaround time of the application is decreased by 83.5% as compared to the existing offloading frameworks. Hence, the proposed framework minimizes additional resources utilization and therefore offers lightweight solution for computational offloading in MCC.


Immunodrugs: breaking B- but not T-cell tolerance with therapeutic anticytokine vaccines.
Pathology in most chronic inflammatory diseases is characterized by an imbalance in cytokine expression. Targeting cytokines with monoclonal antibodies has proven to be a highly effective treatment. However, monoclonal antibody therapy has disadvantages such as high production costs, generation of antimonoclonal antibodies and the inconvenience of frequent injections. Therapeutic vaccines have the potential to overcome these limitations. The aim of active vaccination is to induce B-cell responses and obtain autoantibodies capable of neutralizing the interaction of the targeted cytokine with its receptor. In order to achieve this, therapeutic vaccines need to circumvent the potent tolerance mechanisms that exist to prevent immune responses against self-molecules. This article focuses on the tolerance mechanisms of the B- and T-cell compartments and how these may be manipulated to obtain high-affinity autoantibodies without inducing potentially dangerous autoreactive T-cell responses.


Violent offending by UK military personnel deployed to Iraq and Afghanistan: a data linkage cohort study.
Violent offending by veterans of the Iraq and Afghanistan conflicts is a cause for concern and there is much public debate about the proportion of ex-military personnel in the criminal justice system for violent offences. Although the psychological effects of conflict are well documented, the potential legacy of violent offending has yet to be ascertained. We describe our use of criminal records to investigate the effect of deployment, combat, and post-deployment mental health problems on violent offending among military personnel relative to pre-existing risk factors. In this cohort study, we linked data from 13,856 randomly selected, serving and ex-serving UK military personnel with national criminal records stored on the Ministry of Justice Police National Computer database. We describe offending during the lifetime of the participants and assess the risk factors for violent offending. 2,139 (weighted 17.0%) of 12,359 male UK military personnel had a criminal record for any offence during their lifetime. Violent offenders (1,369 [11.0%]) were the most prevalent offender types; prevalence was highest in men aged 30 years or younger (521 [20.6%] of 2,728) and fell with age (164 [4.7%] of 3027 at age >45 years). Deployment was not independently associated with increased risk of violent offending, but serving in a combat role conferred an additional risk, even after adjustment for confounders (violent offending in 137 [6.3%] of 2178 men deployed in a combat role vs 140 (2.4%) of 5,797 deployed in a non-combat role; adjusted hazard ratio 1.53, 95% CI 1.15-2.03; p=0.003). Increased exposure to traumatic events during deployment also increased risk of violent offending (violent offending in 104 [4.1%] of 2753 men with exposure to two to four traumatic events vs 56 [1.6%] of 2944 with zero to one traumatic event, 1.77, 1.21-2.58, p=0.003; and violent offending in 122 [5.1%] of 2582 men with exposure to five to 16 traumatic events, 1.65, 1.12-2.40, p=0.01; test for trend, p=0.032). Violent offending was strongly associated with post-deployment alcohol misuse (violent offending in 120 [9.0%] of 1363 men with alcohol misuse vs 155 [2.3%] of 6768 with no alcohol misuse; 2.16, 1.62-2.90; p<0.0001), post-traumatic stress disorder (violent offending in 25 [8.6%] of 344 men with post-traumatic stress disorder vs 221 [3.0%] of 7256 with no symptoms of post-traumatic stress disorder; 2.20, 1.36-3.55; p=0.001), and high levels of self-reported aggressive behaviour (violent offending in 56 [6.7%] of 856 men with an aggression score of six to 16 vs 22 [1.2%] of 1685 with an aggression score of zero; 2.47, 1.37-4.46; p=0.003). Of the post-traumatic stress disorder symptoms, the hyperarousal cluster was most strongly associated with violent offending (2.01, 1.50-2.70; p<0.0001). Alcohol misuse and aggressive behaviour might be appropriate targets for interventions, but any action must be evidence based. Post-traumatic stress disorder, though less prevalent, is also a risk factor for violence, especially hyperarousal symptoms, so if diagnosed it should be appropriately treated and associated risk monitored. Medical Research Council and the UK Ministry of Defence.


The Potential of Self-Management mHealth for Pediatric Cystic Fibrosis: Mixed-Methods Study for Health Care and App Assessment.
Remote care services and patient empowerment have boosted mobile health (mHealth). A study of user needs related to mHealth for pediatric cystic fibrosis (PCF) identified the set of preferred features mobile apps should support; however, the potential use of PCF apps and their suitability to fit into PCF clinical management remains unexplored. We examine whether PCF holds potential for the implementation of mHealth care. The study is based on a literature review and qualitative analysis of content and was conducted in two parts: (1) we reviewed scientific and gray literature to explore how European countries manage PCF and conducted a qualitative study of 6 PCF units and (2) we performed a systematic review of apps available in the myhealthapps.net repository searching for cystic fibrosis (CF) management and nutrition apps, which we analyzed for characteristics, business models, number of downloads, and usability. European CF routine care guidelines are acknowledged in most European countries, and treatments are fully covered in almost all countries. The majority of teams in CF units are interdisciplinary. With respect to the systematic review of apps, we reviewed 12 apps for CF management and 9 for general nutrition management in the myhealthapps.net directory. All analyzed apps provided functionalities for recording aspects related to the disease and nutrition such as medication, meals, measurements, reminders, and educational material. None of the apps reviewed in this study supported pancreatic enzyme replacement therapy. CF apps proved to be less appealing and usable than nutrition apps (2.66 [SD 1.15] vs 4.01 [SD 0.90]; P<.001, z-value: -2.6). User needs detected in previous research are partially matched by current apps for CF management. The health care context for PCF is a unique opportunity for the adoption of mHealth. Well-established clinical guidelines, heterogeneous clinical teams, and coverage by national health care systems provide a suitable scenario for the use of mHealth solutions. However, available apps for CF self-management do not cover essential aspects such as nutrition and education. To increase the adoption of mHealth for CF self-management, new apps should include these features. RR2-10.1136/bmjopen-2016-014931.


Practical considerations in the pathologic diagnosis of needle core biopsies of breast.
The success of needle core biopsy procedures and the validity of pathologic diagnoses made on material from the procedures are key determinants in planning the optimal management of a wide variety of breast diseases. The most common diagnostic problems encountered in these biopsy specimens include lobular and ductal proliferations, sclerosing and papillary lesions, cellular fibroepithelial tumors, and minimally invasive or microinvasive carcinoma. This review provides practical guidance to help narrow the differential diagnosis of lesions on needle core biopsies and offers guidelines for the pathologic reporting of these specimens.


Evidence of disseminated intravascular coagulation in a hemorrhagic fever with renal syndrome-scoring models and severe illness.
Viral hemorrhagic fevers (VHF) are considered to be a serious threat to public health worldwide with up to 100 million cases annually. The general hypothesis is that disseminated intravascular coagulation (DIC) is an important part of the pathogenesis. The study objectives were to study the variability of DIC in consecutive patients with acute hemorrhagic fever with renal syndrome (HFRS), and to evaluate if different established DIC-scores can be used as a prognostic marker for a more severe illness. In a prospective study 2006-2008, data from 106 patients with confirmed HFRS were analyzed and scored for the presence of DIC according to six different templates based on criteria from the International Society on Thrombosis and Haemostasis (ISTH). The DIC-scoring templates with a fibrinogen/CRP-ratio were most predictive, with predictions for moderate/severe illness (p<0.01) and bleeding of moderate/major importance (p<0.05). With these templates, 18.9-28.3% of the patients were diagnosed with DIC. DIC was found in about one fourth of the patients and correlated with a more severe disease. This supports that DIC is an important part of the pathogenesis in HFRS. ISTH-scores including fibrinogen/CRP-ratio outperform models without. The high negative predictive value could be a valuable tool for the clinician. We also believe that our findings could be relevant for other VHFs.


Social Stories™ to alleviate challenging behaviour and social difficulties exhibited by children with autism spectrum disorder in mainstream schools: design of a manualised training toolkit and feasibility study for a cluster randomised controlled trial with nested qualitative and cost-effectiveness components.
A Social Story™ (Carol Gray) is a child-friendly intervention that is used to give children with autism spectrum disorders (ASDs) social information in situations where they have social difficulties. Limited evidence mainly using single-case designs suggests that they can reduce anxiety and challenging behaviour. The objectives were to conduct a systematic review, use this to develop a manualised intervention and run a feasibility trial to inform a fully powered randomised controlled trial (RCT) on their clinical effectiveness and cost-effectiveness in schools. This is a three-stage study following the Medical Research Council framework for complex interventions. Specifically, it involved a theoretical phase, a qualitative stage and a feasibility trial stage. Qualitative interviews and focus groups took place in Child and Adolescent Mental Health Service and primary care settings. The feasibility study took place in 37 local mainstream schools. Fifty children (aged 5-15 years) in mainstream school settings with a diagnosis of ASD were entered into the trial. For each child, an associated teacher and parent was also recruited. The intervention was a goal-setting session followed by a manualised toolkit (including a training session) for creating Social Stories™ for use with school-aged children. The comparator treatment was a goal-setting session followed by an attention control. Both arms received treatment as usual. Outcomes tested as part of the feasibility study included child- and proxy-completed questionnaires for mental health, quality of life and goal-based outcome measures. Adults additionally completed behaviour diaries and the parental stress index. The review found that the research into social stories is predominantly based in the USA, carried out in under-12-year-olds and using single-case designs. Most studies either did not follow established Social Story criteria or did not report if they did. The assessment of effectiveness presents a largely positive picture but is limited by methodological issues. There were no adequate RCTs and insufficient information to assess a number of important sources of potential bias in most studies. A manualised intervention was produced using an iterative process between user focus groups and a writing team, and assessed in the feasibility study. All 50 participant groups were recruited within the study time frame. Two outcome measures, the Social Responsiveness Scale-2 and the custom-made goal-based measure, showed high levels of completion rates and appeared to be capturing social and behaviour skills targeted by the use of Social Stories. Detailed recommendations for a full trial are provided. Blinding of participants was not feasible. Treatment fidelity was not assessed because of low levels of story return rates. The study showed that a fully powered RCT is feasible with an extended geographical footprint. A large amount of data and information has helped to inform the design of this RCT, which will be the subject of a future research grant application. Future work could focus on developing an appropriate blinded outcome measure for this population. This study is registered as PROSPERO CRD42011001440. Current Controlled Trials ISRCTN96286707. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 6. See the NIHR Journals Library website for further project information.


Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas.
Capillary hemangioblastoma is the most frequent manifestation of the autosomal dominantly inherited von Hippel-Lindau (VHL) disease but also presents as a nonfamilial, sporadic vascular tumor. Hemangioblastomas are characterized by a dense network of capillaries in association with cysts. To investigate the mechanisms underlying neovascularization and cyst formation, we analyzed eight VHL disease-associated and five sporadic hemangioblastomas. Histologically, both tumor types showed a similar phenotype. The capillaries expressed the endothelial cell markers von Willebrand factor and CD31 antigen. We investigated the expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen which is also known to induce vascular permeability in vivo, and its high affinity tyrosine kinase receptors flt-1 and KDR. Northern blot and in situ hybridization analysis revealed significant up-regulation of VEGF and VEGF receptor expression in VHL disease-associated and sporadic hemangioblastomas compared to normal brain and tumor stromal cells as sites of abundant VEGF transcription. Endothelial cells did not express detectable amounts of VEGF mRNA but coexpressed flt-1 and KDR. By immunohistochemistry, VEGF protein was detectable in the tumor interstitium and was found to be concentrated around capillaries. Performing reverse transcription-PCR, we demonstrated that VEGF121 and VEGF165 were the splice variants predominantly expressed, whereas mRNA encoding VEGF189 was present at smaller amounts. Our findings suggest that, in VHL disease-associated and sporadic hemangioblastomas, VEGF121 and VEGF165 are secreted by stromal cells and interact with the corresponding VEGF receptors expressed on tumor endothelial cells. This paracrine mechanism may mediate neovascularization and cyst formation in capillary hemangioblastomas.


NMR solution structure of subunit F of the methanogenic A1AO adenosine triphosphate synthase and its interaction with the nucleotide-binding subunit B.
The A1AO adenosine triphosphate (ATP) synthase from archaea uses the ion gradients generated across the membrane sector (AO) to synthesize ATP in the A3B3 domain of the A1 sector. The energy coupling between the two active domains occurs via the so-called stalk part(s), to which the 12 kDa subunit F does belong. Here, we present the solution structure of the F subunit of the A1AO ATP synthase from Methanosarcina mazei Gö1. Subunit F exhibits a distinct two-domain structure, with the N-terminal having 78 residues and residues 79-101 forming the flexible C-terminal part. The well-ordered N-terminal domain is composed of a four-stranded parallel beta-sheet structure and three alpha-helices placed alternately. The two domains are loosely associated with more flexibility relative to each other. The flexibility of the C-terminal domain is further confirmed by dynamics studies. In addition, the affinity of binding of mutant subunit F, with a substitution of Trp100 against Tyr and Ile at the very C-terminal end, to the nucleotide-binding subunit B was determined quantitatively using the fluorescence signals of natural subunit B (Trp430). Finally, the arrangement of subunit F within the complex is presented.


Gender differences in use of prescription narcotic medications among living kidney donors.
Prescription narcotic use among living kidney donors is not well described. Using a unique database that integrates national registry identifiers for living kidney donors (1987-2007) in the United States with billing claims from a private health insurer (2000-2007), we identified pharmacy fills for prescription narcotic medications in periods 1-4 and >4 yr post-donation and estimated relative likelihoods of post-donation narcotic use by Cox regression. We also compared narcotic fill rates and medication possession ratios (MPRs, defined as (days of medication supplied)/(days observed)), between donors and age- and sex-matched non-donors. Overall, rates of narcotic medication fills were 32.3 and 32.4 per 100 person-years in periods 1-4 and >4 yr post-donation. After age and race adjustment, women were approximately twice as likely as men to fill a narcotic prescription in years 1-4 (adjusted hazard ratio, aHR, 2.28; 95% confidence interval, CI, 1.86-2.79) and >4 yr (aHR 1.70; 95% CI 1.50-1.93). MPRs in donors were low (<2.5% days exposed), and lower than among age- and sex-matched non-donors. Prescription narcotic medication use is more common among women than men in the intermediate term after live kidney donation. Overall, total narcotic exposure is low, and lower than among non-donors from the general population.


Dysregulated Nox4 ubiquitination contributes to redox imbalance and age-related severity of acute lung injury.
Acute respiratory distress syndrome (ARDS) is a devastating critical illness disproportionately affecting the elderly population, with both higher incidence and mortality. The integrity of the lung endothelial cell (EC) monolayer is critical for preservation of lung function. However, mechanisms mediating EC barrier regulation in the context of aging remain unclear. We assessed the severity of acute lung injury (ALI) in young (2 mo) and aged (18 mo) mice using a two-hit preclinical model. Compared with young cohorts, aged mice exhibited increased ALI severity, with greater vascular permeability characterized by elevated albumin influx and levels of bronchoalveolar lavage (BAL) cells (neutrophils) and protein. Aged/injured mice also demonstrated elevated levels of reactive oxygen species (ROS) in the BAL, which was associated with upregulation of the ROS-generating enzyme, Nox4. We evaluated the role of aging in human lung EC barrier regulation utilizing a cellular model of replicative senescence. Senescent EC populations were defined by increases in β-galactosidase activity and p16 levels. In response to lipopolysaccharide (LPS) challenge, senescent ECs demonstrate exacerbated permeability responses compared with control "young" ECs. LPS challenge led to a rapid induction of Nox4 expression in both control and senescent ECs, which was posttranslationally mediated via the proteasome/ubiquitin system. However, senescent ECs demonstrated deficient Nox4 ubiquitination, resulting in sustained expression of Nox4 and alterations in cellular redox homeostasis. Pharmacological inhibition of Nox4 in senescent ECs reduced LPS-induced alterations in permeability. These studies provide insight into the roles of Nox4/senescence in EC barrier responses and offer a mechanistic link to the increased incidence and mortality of ARDS associated with aging.


Parental smoking during pregnancy, early growth, and risk of obesity in preschool children: the Generation R Study.
Maternal smoking during pregnancy seems to be associated with obesity in offspring. Not much is known about the specific critical exposure periods or underlying mechanisms for this association. We assessed the associations of active maternal and paternal smoking during pregnancy with early growth characteristics and risks of overweight and obesity in preschool children. This study was a population-based, prospective cohort study from early fetal life until the age of 4 y in 5342 mothers and fathers and their children. Growth characteristics [head circumference, length, weight, and body mass index (BMI; in kg/m(2))] and overweight and obesity were repeatedly measured at the ages of 1, 2, 3, and 4 y. In comparison with children from nonsmoking mothers, children from mothers who continued smoking during pregnancy had persistently smaller head circumferences and heights until the age of 4 y, whereas their weights were lower only until the age of 3 mo. This smaller length and normal to higher weight led to an increased BMI [SD score difference: 0.11; 95% CI: 0.02, 0.20; P < 0.05)] and an increased risk of obesity (odds ratio: 1.61; 95% CI: 1.03, 2.53; P < 0.05) at the age of 4 y. In nonsmoking mothers, paternal smoking was not associated with postnatal growth characteristics or risk of obesity in offspring. Maternal smoking during pregnancy was associated with a higher BMI at the age of 4 y in children with a normal birth weight and in those who were small for gestational age at birth. Our findings suggest that direct intrauterine exposure to smoke until late pregnancy leads to different height and weight growth adaptations and increased risks of overweight and obesity in preschool children.


Seasonality and symptoms of depression: A systematic review of the literature.
Lay opinions and published papers alike suggest mood varies with the seasons, commonly framed as higher rates of depression mood in winter. Memory and confirmation bias may have influenced previous studies. We therefore systematically searched for and reviewed studies on the topic, but excluded study designs where explicit referrals to seasonality were included in questions, interviews or data collection. Systematic literature search in Cochrane database, DARE, Medline, Embase, PsychINFO and CINAHL, reporting according to the PRISMA framework, and study quality assessment using the Newcastle-Ottawa scale. Two authors independently assessed each study for inclusion and quality assessment. Due to large heterogeneity, we used a descriptive review of the studies. Among the 41 included studies, there was great heterogeneity in regards to included symptoms and disorder definitions, operationalisation and measurement. We also observed important heterogeneity in how definitions of 'seasons' as well as study design, reporting and quality. This heterogeneity precluded meta-analysis and publication bias analysis. Thirteen of the studies suggested more depression in winter. The remaining studies suggested no seasonal pattern, seasonality outside winter, or inconclusive results. The results of this review suggest that the research field of seasonal variations in mood disorders is fragmented, and important questions remain unanswered. There is some support for seasonal variation in clinical depression, but our results contest a general population shift towards lower mood and more sub-threshold symptoms at regular intervals throughout the year. We suggest future research on this issue should be aware of potential bias by design and take into account other biological and behavioural seasonal changes that may nullify or exacerbate any impact on mood.


Zero TE MR bone imaging in the head.
To investigate proton density (PD)-weighted zero TE (ZT) imaging for morphological depiction and segmentation of cranial bone structures. A rotating ultra-fast imaging sequence (RUFIS) type ZT pulse sequence was developed and optimized for 1) efficient capture of short T2 bone signals and 2) flat PD response for soft-tissues. An inverse logarithmic image scaling (i.e., -log(image)) was used to highlight bone and differentiate it from surrounding soft-tissue and air. Furthermore, a histogram-based bias-correction method was developed for subsequent threshold-based air, soft-tissue, and bone segmentation. PD-weighted ZT imaging in combination with an inverse logarithmic scaling was found to provide excellent depiction of cranial bone structures. In combination with bias correction, also excellent segmentation results were achieved. A two-dimensional histogram analysis demonstrates a strong, approximately linear correlation between inverse log-scaled ZT and low-dose CT for Hounsfield units (HU) between -300 HU and 1,500 HU (corresponding to soft-tissue and bone). PD-weighted ZT imaging provides robust and efficient depiction of bone structures in the head, with an excellent contrast between air, soft-tissue, and bone. Besides structural bone imaging, the presented method is expected to be of relevance for attenuation correction in positron emission tomography (PET)/MR and MR-based radiation therapy planning.


Effectiveness of a School Based Smokeless Tobacco Intervention: A Cluster Randomized Trial.
To assess the effectiveness of intervention in improving knowledge, attitude and perception regarding smokeless tobacco (SLT) use and its harmful effects and intention to quit SLT among school going adolescents. A school-based cluster randomized control trial was carried out in 18 secondary schools targeting male and female students from grades 6 to 10 in Karachi. Primary outcome was knowledge about hazards of smokeless tobacco (SLT) and secondary outcomes were attitude and Perception about hazards of SLT, and intention to quit SLT. We enrolled 738 participants in intervention group and 589 in the control group. Mean score of knowledge significantly improved in intervention as compared to control group (P value < 0.01). Intention to quit was found to be proportionately higher (33%) in the intervention group as compared to control group. Generalized estimating equations were used to assess the association of factors with knowledge regarding harmful effects of SLT use. Significant predictors of increase in knowledge score were found in children: who had seen any anti SLT messages on social media in the past 30 days, who were getting information regarding harmful effects of SLT use in school or textbooks and who had friends using SLT. A school-based intervention was effective in increasing knowledge regarding the harmful effects of SLT use and intention to quit SLT use among school adolescents. Introduction of such educational programmes on a regular basis in schools or as part of school curriculum can have an impact on reducing prevalence of SLT use.Trial Registration NCT03418506. https://register.clinicaltrials.gov/NCT03418506 .


Greenlighting photoelectrochemical oxidation of water by iron oxide.
Hematite (α-Fe2O3) is one of just a few candidate electrode materials that possess all of the following photocatalyst-essential properties for scalable application to water oxidation: excellent stability, earth-abundance, suitability positive valence-band-edge energy, and significant visible light absorptivity. Despite these merits, hematite's modest oxygen evolution reaction kinetics and its poor efficiency in delivering photogenerated holes, especially holes generated by green photons, to the electrode/solution interface, render it ineffective as a practical water-splitting catalyst. Here we show that hole delivery and catalytic utilization can be substantially improved through Ti alloying, provided that the alloyed material is present in ultrathin-thin-film form. Notably, the effects are most pronounced for charges photogenerated by photons with energy comparable to the band gap for excitation of Fe(3d)→Fe(3d) transitions (i.e., green photons). Additionally, at the optimum Ti substitution level the lifetimes of surface-localized holes, competent for water oxidation, are extended. Together these changes explain an overall improvement in photoelectrochemical performance, especially enhanced internal quantum efficiencies, observed upon Ti(IV) incorporation.


The Iowa radon lung cancer study--phase I: Residential radon gas exposure and lung cancer.
Exposure to high concentrations of radon (222Rn) progeny produces lung cancer in both underground miners and experimentally-exposed laboratory animals. The goal of the study was to determine whether or not residential radon exposure exhibits a statistically significant association with lung cancer in a state with high residential radon concentrations. A population-based, case-control epidemiologic study was conducted examining the relationship between residential radon gas exposure and lung cancer in Iowa females who occupied their current home for at least 20 years. The study included 413 incident lung cancer cases and 614 age-frequency-matched controls. Participant information was obtained by a mailed-out questionnaire with face-to-face follow-up. Radon dosimetry assessment consisted of five components: (1) on-site residential assessment survey; (2) on-site radon measurements; (3) regional outdoor radon measurements; (4) assessment of subjects' exposure when in another building; and (5) linkage of historic subject mobility with residential, outdoor, and other building radon concentrations. Histologic review was performed for 96% of the cases. Approximately 60% of the basement radon concentrations and 30% of the first floor radon concentrations of study participants' homes exceeded the US Environmental Protection Agency action level of 150 Bq m(-3) (4 pCi l(-1)). Large areas of western Iowa had outdoor radon concentrations comparable to the national average indoor value of 55 Bq m(-3) (1.5 pCi l(-1)). Excess odds of 0.24 (95% CI = -0.05-0.92) and 0.49 (95% CI = 0.03-1.84) per 11 WLM(5-19) were calculated using the continuous radon exposure estimates for all cases and live cases, respectively. Slightly higher excess odds of 0.50 (95% CI = 0.004-1.80) and 0.83 (CI = 0.11-3.34) per 11 WLM(5-19) were noted for the categorical radon exposure estimates for all cases and the live cases. A positive association between cumulative radon gas exposure and lung cancer was demonstrated using both categorical and continuous analyses. The risk estimates obtained in this study indicate that cumulative radon exposure presents an important environmental health hazard.


Sensory modulation and sleep quality among adults with learning disabilities: a quasi-experimental case-control design study.
Following the International Classification of Functioning, Disability and Health (ICF) concepts, this study examines body functions such as sensory modulation and sleep quality among adults with learning disabilities (LD). One hundred and ten participants, 55 adults with LD and 55 matched controls (mean age 30 years) filled in a socio-demographic questionnaire, the Adults/Adolescents Sensory Profile (AASP), and the Mini Sleep Questionnaire (MSQ). Chi-tests, Mann-Whitney tests, and Kolmogorov-Smirnov tests were conducted to examine group differences related to socio-demographic characteristics and body functions. Correlation and regression analyses were conducted to examine relationships between body functions. Significant differences were found between the groups in: (a) unique socio-demographic variables: high-schools attended, family status and number of children; (b) body functions: low registration and sensory sensitivity (p < .001), sensory avoiding (p = .002), sensory seeking (p = .021) and sleep quality (p < .001). Significant correlations were found between AASP subscale scores and the MSQ final score in each group. Regression analysis revealed that for the entire sample (N = 108), low registration accounted for 10.2% of the variance of sleep quality above group membership (p < .001), while in a separate examination of adults with LD (n = 53), low registration accounted for 19.9% of the variance of sleep quality (p < .001). Adults with LD need to be studied through a health-related perspective such as the ICF model to gain further understanding of their unique characteristics and daily needs. Sensory and sleep functions of adults with LD should be further studied in the context of health related quality of life.


Evaluating the process of polishing borosilicate glass capillaries used for fabrication of in-vitro fertilization (iVF) micro-pipettes.
In this paper we investigate a number of gas flames for fire polishing borosilicate glass capillaries used in the manufacturing of IVF micro-pipettes. Hydrofluoric acid (HF) was also used as an alternative to finish the pipette end. Glass micro tools in the IVF industry are drawn from hollow glass capillaries of diameter 1 mm. These capillaries are cut manually to a length of 100 mm from hollow glass rods resulting in sharp and chipped edges. These capillaries are held in a customised holder having padding of soft silicone or rubber. Sharp and uneven edges of these capillaries pick up particles of rubber or soft silicone shavings, rendering them ineffective for IVF treatments. The working range of borosilicate glass is 800-1,200 degrees C. The experiments involved analysis of fire polishing process for borosilicate glass capillaries using candle, butane, propane, 2350 butane propane, oxyacetylene gas flames, finding the optimum distance of the capillary relative to the flame, optimum time for which the capillary should be held in the flame and optimum region of the flame which gives the required temperature range. The results show that 2350 butane propane gas mix is optimum for fire polishing of borosilicate glass capillaries. The paper is concluded by comparing the results of fire polishing with the results of acid polishing, in which HF of 1.6% concentration is used to etch the ends of the borosilicate glass pipettes.


Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial.
Head-to-head trials to guide antipsychotic treatment choices for paediatric psychosis are urgently needed because extrapolations from adult studies might not be implementable. In this superiority trial with two-sided significance testing, we aimed to compare the efficacy and safety of quetiapine-extended release (quetiapine-ER) versus aripiprazole in children and adolescents with first-episode psychosis, to determine whether differences between the two treatments were sufficient to guide clinicians in their choice of one drug over the other. In this multicentre, double-blind, randomised trial in seven Danish university clinics, we recruited children and adolescents aged 12-17 years with a diagnosis of ICD-10 schizophrenia-spectrum disorder, delusional disorder, or affective-spectrum psychotic disorder, and psychotic symptoms scoring at least 4 on at least one of the following Positive and Negative Syndrome Scale (PANSS) items: P1 (delusions), P2 (conceptual disorganisation), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution), and G9 (unusual thought content), and a total PANSS score greater than 60. Patients were randomly assigned (1:1) to 12 weeks of treatment with target doses of 600 mg/day of quetiapine-ER (starting from 50 mg/day) or 20 mg/day of aripiprazole (starting from 2·5 mg/day). The assigned drug was titrated over five levels, with 2 days at each dose, and the final dose achieved on day 9. Randomisation was done using a computer-generated concealed sequence with a block size of 8, and stratified by baseline PANSS positive score (≤20 points or >20 points) and age (12-14 years or 15-17 years). Study drugs were administered in identical capsules, and interventions, assessments, and data analysis were done masked. The primary outcome was PANSS positive score. Key adverse outcomes were bodyweight, homoeostatic model of insulin resistance (HOMA-IR), akathisia, and sedation. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01119014. Between June 10, 2010, and Jan 29, 2014, 231 participants were assessed for elegibility, of whom 113 were randomly assigned to quetiapine-ER (n=55) or aripiprazole (n=58). PANSS positive score did not differ between groups after 12 weeks (adjusted mean change -5·05 [5·46] for quetiapine-ER, -6·21 [5·42] for aripiprazole; p=0·98), but decreased over time in both groups (p<0·0001). Weight gain was more rapid with quetiapine-ER (p=0·0008), with an adjusted mean weight group difference at week 12 of 3·33 kg (SD 7·23; effect size 0·64; p<0·0001). The HOMA-IR group difference at week 12 favoured aripiprazole (adjusted mean log-transformed group difference 0·259 [SD 0·906]; effect size 0·35; p=0·0060). Akathisia was more common with aripiprazole at week 2 (observed in 34 [60%] of 57 patients; estimated 63·5%) than with quetiapine-ER (15 [30%] of 50; estimated 31·3%; p=0·0021), but not at other timepoints. Sedation proportions did not change significantly over time with either intervention (observed at weeks 2, 4, and 12, respectively, for quetiapine-ER in 43 [83%] of 52, 40 [83%] of 48, and 34 [72%] of 47 patients and for aripiprazole in 49 [89%] of 55, 52 [96%] of 54, and 44 [92%] of 48 patients), and the overall estimated probability combining all timepoints was significantly higher for aripiprazole (97·1%) than for quetiapine-ER (89·2%; p=0·012). In addition to sedation and akathisia, the most common adverse events were tremor (42 [79%] patients in the quetiapine-ER group vs 52 [91%] patients in the aripiprazole group), increased duration of sleep (47 [92%] vs 39 [71%]), orthostatic dizziness (42 [78%] vs 46 [81%]), depression (43 [80%] vs 44 [77%]), tension/inner unrest (37 [69%] vs 50 [88%]), failing memory (41 [76%] vs 44 [77%]), and weight gain (46 [87%] vs 38 [68%]). This first head-to-head comparison of quetiapine-ER versus aripiprazole in early-onset psychosis showed no significant group differences in severity of psychopathology after 12 weeks of treatment. Quetiapine-ER was associated with more metabolic adverse events and aripiprazole with more initial akathisia and, unexpectedly, more sedation. The limited antipsychotic efficacy and high level of adverse events were noticeable. This trial provides novel information for the treatment of early-onset psychosis and highlights the importance of adverse event profiles when choosing among antipsychotics for children and adolescents who often require chronic treatment. The National Research Council for Health and Disease Foundation for Health Promotion, AP Møller Foundation, Rosalie Petersens Foundation, Stevn and Rindom Foundation, Foundation for the Promotion of Medical Science, The Capital Region Psychiatric Research Foundation, Tryg Foundation, Region of Southern Denmark Research Foundation, Danish Psychiatric Research Educational Fund, Psychiatry Foundation, Foundation of 17-12-1981, Psychiatric Research Foundation Region Zealand, Capital Region Strategic Research Foundation, Knud og Dagny Andresens Foundation, Psychiatric Research Foundation of 1967, The Capital Region Research Foundation, Dr Sofus Carl Emil Friis and Hustru Olga Friis Scholarship, Tømrerhandler Johannes Fogs Foundation, Brdr Hartmanns Foundation DKK, Aase and Ejnar Danielsens Foundation, Jacob Madsen and wife Olga Madsens Foundation, CC Klestrup and wife Scholarship, Lundbeck Foundation Scholarship, and Tømrermester Jørgen Holm and wife Elisas Scholarship.


The hemagglutinin of canine distemper virus determines tropism and cytopathogenicity.
Canine distemper virus (CDV) and measles virus (MV) cause severe illnesses in their respective hosts. The viruses display a characteristic cytopathic effect by forming syncytia in susceptible cells. For CDV, the proficiency of syncytium formation varies among different strains and correlates with the degree of viral attenuation. In this study, we examined the determinants for the differential fusogenicity of the wild-type CDV isolate 5804Han89 (CDV(5804)), the small- and large-plaque-forming variants of the CDV vaccine strain Onderstepoort (CDV(OS) and CDV(OL), respectively), and the MV vaccine strain Edmonston B (MV(Edm)). The cotransfection of different combinations of fusion (F) and hemagglutinin (H) genes in Vero cells indicated that the H protein is the main determinant of fusion efficiency. To verify the significance of this observation in the viral context, a reverse genetic system to generate recombinant CDVs was established. This system is based on a plasmid containing the full-length antigenomic sequence of CDV(OS). The coding regions of the H proteins of all CDV strains and MV(Edm) were introduced into the CDV and MV genetic backgrounds, and recombinant viruses rCDV-H(5804), rCDV-H(OL), rCDV-H(Edm), rMV-H(5804), rMV-H(OL), and rMV-H(OS) were recovered. Thus, the H proteins of the two morbilliviruses are interchangeable and fully functional in a heterologous complex. This is in contrast with the glycoproteins of other members of the family Paramyxoviridae, which do not function efficiently with heterologous partners. The fusogenicity, growth characteristics, and tropism of the recombinant viruses were examined and compared with those of the parental strains. All these characteristics were found to be predominantly mediated by the H protein regardless of the viral backbone used.


Design and validation of a new Healthcare Systems Usability Scale (HSUS) for clinical decision support systems: a mixed-methods approach.
To develop and validate a questionnaire to assess the usability of clinical decision support systems (CDSS) and to assist in the early identification of usability issues that may impact patient safety and quality of care. Mixed research methods were used to develop and validate the questionnaire. The qualitative study involved scale item development, content and face validity. Pilot testing established construct validity using factor analysis and facilitated estimates for reliability and internal consistency using the Cronbach's alpha coefficient. Two hospitals within a single National Health Service Trust. We recruited a panel of 7 experts in usability and questionnaire writing for health purposes to test content validity; 10 participants to assess face validity and 78 participants for the pilot testing. To be eligible for this last phase, participants needed to be health professionals with at least 3 months experience using the local hospital electronic patient record system. Feedback from the face and content validity phases contributed to the development and improvement of scale items. The final Healthcare Systems Usability Scale (HSUS) proved quick to complete, easy to understand and was mostly worded by potential users. Exploratory analysis revealed four factors related to patient safety, task execution, alerts or recommendations accuracy, the effects of the system on workflow and ease of system use. These separate into four subscales: patient safety and decision effectiveness (seven items), workflow integration (six items), work effectiveness (five items) and user control (four items). These factors affect the quality of care and clinician's ability to make informed and timely decisions when using CDSS. The HSUS has a very good reliability with global Cronbach's alpha 0.914 and between 0.702 and 0.926 for the four subscales. The HSUS is a valid and reliable tool for usability testing of CDSS and early identification of usability issues that may cause medical adverse events.


ProtEx technology for the generation of novel therapeutic cancer vaccines.
Therapeutic vaccines present an attractive alternative to conventional treatments for cancer. However, tumors have evolved various immune evasion mechanisms to modulate innate, adaptive, and regulatory immunity for survival. Therefore, successful vaccine formulations may require a non-toxic immunomodulator or adjuvant that not only induces/stimulates innate and adaptive tumor-specific immune responses, but also overcomes immune evasion mechanisms. Given the paramount role costimulation plays in modulating innate, adaptive, and regulatory immune responses, costimulatory ligands may serve as effective immunomodulating components of therapeutic cancer vaccines. Our laboratory has developed a novel technology designated as ProtEx that allows for the generation of recombinant costimulatory ligands with potent immunomodulatory activities and the display of these molecules on the cell surface in a rapid and efficient manner as a practical and safe alternative to gene therapy for immunomodulation. Importantly, the costimulatory ligands not only function when displayed on tumor cells, but also as soluble proteins that can be used as immunomodulatory components of conventional vaccine formulations containing tumor-associated antigens (TAAs). We herein discuss the application of the ProtEx technology to the development of effective cell-based as well as cell-free conventional therapeutic cancer vaccines.


Determining origin in a migratory marine vertebrate: a novel method to integrate stable isotopes and satellite tracking.
Stable isotope analysis is a useful tool to track animal movements in both terrestrial and marine environments. These intrinsic markers are assimilated through the diet and may exhibit spatial gradients as a result of biogeochemical processes at the base of the food web. In the marine environment, maps to predict the spatial distribution of stable isotopes are limited, and thus determining geographic origin has been reliant upon integrating satellite telemetry and stable isotope data. Migratory sea turtles regularly move between foraging and reproductive areas. Whereas most nesting populations can be easily accessed and regularly monitored, little is known about the demographic trends in foraging populations. The purpose of the present study was to examine migration patterns of loggerhead nesting aggregations in the Gulf of Mexico (GoM), where sea turtles have been historically understudied. Two methods of geographic assignment using stable isotope values in known-origin samples from satellite telemetry were compared: (1) a nominal approach through discriminant analysis and (2) a novel continuous-surface approach using bivariate carbon and nitrogen isoscapes (isotopic landscapes) developed for this study. Tissue samples for stable isotope analysis were obtained from 60 satellite-tracked individuals at five nesting beaches within the GoM. Both methodological approaches for assignment resulted in high accuracy of foraging area determination, though each has advantages and disadvantages. The nominal approach is more appropriate when defined boundaries are necessary, but up to 42% of the individuals could not be considered in this approach. All individuals can be included in the continuous-surface approach, and individual results can be aggregated to identify geographic hotspots of foraging area use, though the accuracy rate was lower than nominal assignment. The methodological validation provides a foundation for future sea turtle studies in the region to inexpensively determine geographic origin for large numbers of untracked individuals. Regular monitoring of sea turtle nesting aggregations with stable isotope sampling can be used to fill critical data gaps regarding habitat use and migration patterns. Probabilistic assignment to origin with isoscapes has not been previously used in the marine environment, but the methods presented here could also be applied to other migratory marine species.


Regulation of cerebral blood flow.
The control of cerebral blood flow is complex, and only beginning to be elucidated. Studies have identified three key regulatory paradigms. The first is cerebral pressure autoregulation, which maintains a constant flow in the face of changing cerebral perfusion pressure. Flow-metabolism coupling refers to the brains ability to vary blood flow to match metabolic activity. An extensive arborization of perivascular nerves also serves to modulate cerebral blood flow, so-called neurogenic regulation. Central to these three paradigms are two cell types: endothelium and astrocytes. The endothelium produces several vasoactive factors that are germane to the regulation of cerebral blood flow: nitric oxide, endothelium-dependent hyperpolarization factor, the eicosanoids, and the endothelins. Astrocytic foot processes directly abut the blood vessels, and play a key role in regulation of cerebral blood flow. Lastly, new research has been investigating cell-cell communication at the microvascular level. Several lines of evidence point to the ability of the larger proximal vessels to coordinate vasomotor responses downstream.


Exogenous ammonium inhibits petal pigmentation and expansion in Gerbera hybrida.
Petal pigmentation is the most important aspect in natural flower coloration. In the present study, the inhibition of petal pigmentation by exogenous ammonium was investigated. Ray floret petals detached from inflorescences of Gerbera hybrida (Shenzhen No. 5) were cultured in vitro on media supplied with different forms of nitrogen and its assimilated compounds. The expression of a set of genes involved in anthocyanin biosynthesis and regulation was determined by Northern blotting assay. It was found that ammonium (NH4+), not nitrate (NO3-), in millimolar concentrations inhibited anthocyanin accumulation. The expressions of Gerbera chalcone synthase 1 (GCHS1), Gerbera chalcone synthase 2 (GCHS2) and Gerbera dihydroflavonol-4-reductase (GDFR) decreased, while six other related genes showed no significant changes after NH4+ treatment. Further studies on NH4+ function indicated that glutamine (Gln) acted as a downstream factor of NH4+ to suppress petal pigmentation. Both exogenous Gln and NH4+ were found to inhibit anthocyanin accumulation in the petals, and the application of Gln was also found to inhibit the expressions of GCHS1, GCHS2 and GDFR. The application of NH4+ also resulted in an increase in the activity of Gerbera glutamine synthetase (EC 188.8.131.52) along with a rapid increase of Gln content. When methionine sulfoximine, an inhibitor of glutamine synthetase (GS), was added, it was found to block the NH4+-induced inhibition of pigmentation. From these experiments, we conclude that the NH4+-induced suppression of petal pigmentation is not because of NH4+ toxicity, and the inhibition of pigmentation caused by the addition of exogenous NH4+ is the result of its assimilation into Gln.


The hydrodynamics of dolphin drafting.
Drafting in cetaceans is defined as the transfer of forces between individuals without actual physical contact between them. This behavior has long been surmised to explain how young dolphin calves keep up with their rapidly moving mothers. It has recently been observed that a significant number of calves become permanently separated from their mothers during chases by tuna vessels. A study of the hydrodynamics of drafting, initiated in the hope of understanding the mechanisms causing the separation of mothers and calves during fishing-related activities, is reported here. Quantitative results are shown for the forces and moments around a pair of unequally sized dolphin-like slender bodies. These include two major effects. First, the so-called Bernoulli suction, which stems from the fact that the local pressure drops in areas of high speed, results in an attractive force between mother and calf. Second is the displacement effect, in which the motion of the mother causes the water in front to move forwards and radially outwards, and water behind the body to move forwards to replace the animal's mass. Thus, the calf can gain a 'free ride' in the forward-moving areas. Utilizing these effects, the neonate can gain up to 90% of the thrust needed to move alongside the mother at speeds of up to 2.4 m/sec. A comparison with observations of eastern spinner dolphins (Stenella longirostris) is presented, showing savings of up to 60% in the thrust that calves require if they are to keep up with their mothers. A theoretical analysis, backed by observations of free-swimming dolphin schools, indicates that hydrodynamic interactions with mothers play an important role in enabling dolphin calves to keep up with rapidly moving adult school members.


Is Herpes Simplex virus (HSV) a sign of Encephalitis in Iranian Newborns? Prevalence of HSV Infection in Pregnant Women in Iran: A Systematic Review and Meta-Analysis.
Herpes Simplex virus (HSV) is one of the most common sexually transmitted diseases in the world. This study aimed to determine the prevalence of herpes simplex virus in pregnant women in Iran. A systematic literature review was conducted to study the HSV subtypes in Persian and English papers through several databases. We searched Pub Med, Scopus, Ovid, Science Direct and national databases as Magiran, Iranmedex and Science Information Database (SID) up to October 2015. Random-effects model were applied to calculate the pooled prevalence of HSV subtypes. Five eligible studies were identified, including 1140 participants. The pooled prevalence of HSV infection in pregnant women was 0.64% (95% CI: 0.10- 1.18) in Iran. The pooled prevalence of studies on both HSV-1 and HSV-2 was 0.91% (CI: 0.81-1.02) and studies on only HSV-2 was 0.23% (CI: -0.61-0.63), respectively. The prevalence of HSV infection in pregnant women in Iran was higher. HSV infection of the central nervous system, especially with HSV-2, can also cause recurrent aseptic meningitis and monophasic, as well as radiuculitis or myelitis. The performance of screening to detect infection in pregnant women can play an important role in the prevention and treatment of patients and help to prevent the transmission of HSV infection to infants in Iran.


That which does not kill you makes you stronger: a molecular mechanism for preconditioning.
Preconditioning by sublethal stress can protect a cell from subsequent injury and apoptosis through a mechanism that has been unclear. Many such stresses stimulate the formation of stress granules: transient cytoplasmic foci that contain heat shock protein as well as translationally stalled mRNA and various mRNA-binding proteins. Recent research suggests that sequestration in stress granules of TRAF2, an adaptor protein that is required for tumor necrosis factor receptor 1 signaling, may underlie preconditioning by sublethal stresses.


Effects of vasopressor agents on the development of pressure ulcers in critically ill patients: a systematic review.
The primary objective of this systematic review was to determine the effect of vasopressor agents on the development of pressure ulcers (PUs) among critically ill patients in intensive care units (ICUs). The secondary outcome of interest was length of stay in the ICU. A systematic review was undertaken using the databases searched: Medline, Embase, CINAHL and The Cochrane Library. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to formulate the review. Data were extracted using a predesigned data extraction table and analysed as appropriate using RevMan. Quality appraisal was undertaken using the EBL Critical Appraisal Tool. The inclusion criteria were met by 13 studies. Two studies provided sufficient data to compare the number of patients who developed a PU with and without the use of vasopressors. Consistently, within these two studies, being treated with a vasopressor increased the likelihood of PU development. RevMan analysis identified that shorter duration of administration of vasopressors was associated with less PU development (mean difference (MD) 65.97 hours, 95% confidence interval (CI): 43.47-88.47; p=0.0001). Further, a lower dose of vasopressors was also associated with less PU development (MD: 8.76μg/min, 95% CI: 6.06-11.46; p<0.00001). Mean length of stay increased by 11.46 days for those with a PU compared to those without a PU (MD: 11.46 days; 95% CI: 7.10-15.82; p<0.00001). The overall validities of the studies varied between 45-90%, meaning that there is potential for bias within all the included studies. Vasopressor agents can contribute to the development of PUs in critically ill patients in ICUs. Prolonged ICU stay was also associated with pressure ulcers in this specific patient group. Given the risk of bias within the included studies, further studies are needed to validate the findings of this review paper.


Intraindividual double-burden of anthropometric undernutrition and "metabolic obesity" in Indian children: a paradox that needs action.
Intra-individual coexistence of anthropometrically defined undernutrition and 'metabolic obesity', characterised by presence of at least one abnormal cardiometabolic risk factor, is rarely investigated in young children and adolescents, particularly in Low-and-Middle-Income-Countries undergoing rapid nutrition transition. Prevalence of biomarkers of metabolic obesity was related to anthropometric and socio-demographic characteristics in 5-19 years old participants from the population-based Comprehensive National Nutrition Survey in India (2016-2018). The biomarkers, serum lipid-profile (total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides), fasting glucose, and glycosylated hemoglobin (HbA1C), and all jointly were analysed in 22567, 23192, 25962 and 19143 participants, respectively. Overall (entire dataset), the prevalence of abnormalities was low (4.3-4.5%) for LDL and TC, intermediate for dysglycemia (10.9-16.1%), and high for HDL and triglycerides (21.7-25.8%). Proportions with ≥1 abnormal metabolic obesity biomarker(s) were 56.2% overall, 54.2% in thin (BMI-for-age < -2 SD) and 59.3% in stunted (height-for-age < -2 SD) participants. Comparable prevalence was evident in mild undernutrition (-1 to -2 SD). Clustering of two borderline abnormalities occurred in one-third, warranting active life-style interventions. Metabolic obesity prevalence increased with BMI-for-age. Among those with metabolic obesity, only 9% were overweight/obese (>1 SD BMI-for-age). Among poor participants, triglyceride, glucose and HDL abnormalities were higher. A paradoxical, counter-intuitive prevalence of metabolic obesity biomarker(s) exists in over half of anthropometrically undernourished and normal-weight Indian children and adolescents. There is a crucial need for commensurate investments to address overnutrition along with undernutrition. Nutritional status should be characterized through additional reliable biomarkers, instead of anthropometry alone.


Direct observation of distinct A/P hybrid-state tRNAs in translocating ribosomes.
Transfer RNAs (tRNAs) link the genetic code in the form of messenger RNA (mRNA) to protein sequence. Translocation of tRNAs through the ribosome from aminoacyl (A) site to peptidyl (P) site and from P site to exit site is catalyzed in eukaryotes by the translocase elongation factor 2 (EF-2) and in prokaryotes by its homolog EF-G. During tRNA movement one or more "hybrid" states (A/P) is occupied, but molecular details of them and of the translocation process are limited. Here we show by cryo-electron microscopy that a population of mammalian ribosomes stalled at an mRNA pseudoknot structure contains structurally distorted tRNAs in two different A/P hybrid states. In one (A/P'), the tRNA is in contact with the translocase EF-2, which induces it. In the other (A/P''), the translocase is absent. The existence of these alternative A/P intermediate states has relevance to our understanding of the mechanics and kinetics of translocation.


Central pattern generators and the control of rhythmic movements.
Central pattern generators are neuronal circuits that when activated can produce rhythmic motor patterns such as walking, breathing, flying, and swimming in the absence of sensory or descending inputs that carry specific timing information. General principles of the organization of these circuits and their control by higher brain centers have come from the study of smaller circuits found in invertebrates. Recent work on vertebrates highlights the importance of neuro-modulatory control pathways in enabling spinal cord and brain stem circuits to generate meaningful motor patterns. Because rhythmic motor patterns are easily quantified and studied, central pattern generators will provide important testing grounds for understanding the effects of numerous genetic mutations on behavior. Moreover, further understanding of the modulation of spinal cord circuitry used in rhythmic behaviors should facilitate the development of new treatments to enhance recovery after spinal cord damage.


Network on veterinary medicines initiated by the European Federation For Pharmaceutical Sciences.
The European Federation for Pharmaceutical Sciences (EUFEPS) was founded 25 years ago by more than 20 national pharmaceutical societies and faculty members. As a pan-European organization, it brings together pharmaceutical societies as well as academic, industrial and regulatory scientists engaged in drug research and development, drug regulation and education of professionals working in these fields. EUFEPS represents pharmaceutical sciences in Europe and is recognized as such by both the European Commission and the European Medicines Agency. EUFEPS cooperates with the European Federation of Pharmaceutical Industries and other European organizations and maintains global connections with agencies such as the US Food and Drug Administration and the American Association of Pharmaceutical Scientists. EUFEPS has established specified networks forming the basis of its activities. The creation of a Network on Veterinary Medicines is prompted by the manifold problems resulting from the use of veterinary drugs and its inherent interconnections with human medicine, environmental and public health. A long-term goal of this initiative was to expand the spectrum of available therapeutics for use in animals, including the development of innovative delivery systems.


Dairy proteins, dairy lipids, and postprandial lipemia in persons with abdominal obesity (DairyHealth): a 12-wk, randomized, parallel-controlled, double-blinded, diet intervention study.
Abdominal obesity and exaggerated postprandial lipemia are independent risk factors for cardiovascular disease (CVD) and mortality, and both are affected by dietary behavior. We investigated whether dietary supplementation with whey protein and medium-chain saturated fatty acids (MC-SFAs) improved postprandial lipid metabolism in humans with abdominal obesity. We conducted a 12-wk, randomized, double-blinded, diet intervention study. Sixty-three adults were randomly allocated to one of 4 diets in a 2 × 2 factorial design. Participants consumed 60 g milk protein (whey or casein) and 63 g milk fat (with high or low MC-SFA content) daily. Before and after the intervention, a high-fat meal test was performed. We measured changes from baseline in fasting and postprandial triacylglycerol, apolipoprotein B-48 (apoB-48; reflecting chylomicrons of intestinal origin), free fatty acids (FFAs), insulin, glucose, glucagon, glucagon-like peptide 1 (GLP-1), and gastric inhibitory polypeptide (GIP). Furthermore, changes in the expression of adipose tissue genes involved in lipid metabolism were investigated. Two-factor ANOVA was used to examine the difference between protein types and fatty acid compositions, as well as any interaction between the two. Fifty-two participants completed the study. We found that the postprandial apoB-48 response decreased significantly after whey compared with casein (P = 0.025) independently of fatty acid composition. Furthermore, supplementation with casein resulted in a significant increase in the postprandial GLP-1 response compared with whey (P = 0.003). We found no difference in postprandial triacylglycerol, FFA, insulin, glucose, glucagon, or GIP related to protein type or MC-SFA content. We observed no interaction between milk protein and milk fat on postprandial lipemia. We found that a whey protein supplement decreased the postprandial chylomicron response compared with casein in persons with abdominal obesity, thereby indicating a beneficial impact on CVD risk. This trial was registered at clinicaltrials.gov as NCT01472666.


Amniotic membrane modulates innate immune response inhibiting PRRs expression and NF-κB nuclear translocation on limbal myofibroblasts.
Corneal damage observed in a viral infection such as herpetic stromal keratitis is mainly caused by proinflammatory molecules released by resident cells in the response to viral antigens. There are pattern recognition receptors like MDA5, RIG-1, and TLR3, that recognize viral dsRNA and after activation, the innate immune response is exacerbated inducing the synthesis and secretion of inflammatory cytokines through NF-κB activation. Amniotic membrane (AM) has demonstrated to reduce inflammation by several mechanisms, however the effect of AM on innate immune receptors such as MDA5, RIG-1, and TLR3 has not been reported. In this study, we have determined that the presence of AM significantly inhibited the synthesis and secretion of proinflammatory cytokines on human limbal myofibroblasts (HLM) stimulated with poly I:C. Similarly, the presence of AM reduced the protein expression of MDA5, RIG-1, and TLR3 on poly I:C stimulated HLM. Additionally, the presence of the AM significantly inhibited the NF-κB nuclear translocation when the HLM were poly I:C stimulated, and concomitantly, the AM was able to relocate cadherins affecting the myofibroblastic cellular morphology. These results suggest that AM generates an anti-inflammatory microenvironment, and specific inhibition of NFκB nuclear translocation on infected corneal tissue would reduce the inflammation undesirable effects, explaining in part the beneficial usefulness of transplanting AM on herpetic stromal keratitis.


Hormonal characteristics of the human menstrual cycle throughout reproductive life.
The changes in serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FHS), estradiol, and progesterone that occur both early and late in reproductive life were characterized and compared with findings in young, normal women and in patients with certain menstrual disorders. A total of 50 complete menstrual cycles in 37 were examined. Five distinct patterns of hormonal regulation were found, three of which are reported here: (a) A long follicular phase and delayed follicular maturation in young women with long, unpredictable intermenstrual intervals from menarche; (b) a short follicular phase with increasing age and in short cycles in perimenopausal women; and (c) true anovulatory vaginal bleeding in long cycles in perimenopausal women. The short cycles before and during the menopausal transition were found to have lower E2 levels and high FSH concentrations throughout, while LH remained in the normal range. During long cycles in perimenopausal women, concentrations of LH and FSH were in the menopausal range. However, follicular maturation was observed months after high levels of gonadotropins were attained. These studies permit the characterization of the menstrual history of the normal woman in terms of the hormonal changes that occur and provide a basis for the definition of several disorders of follicular maturation.


Defects of urogenital development in mice lacking Emx2.
The homeobox gene Emx2 is a mouse homologue of a Drosophila head gap gene empty spiracles (ems) and is essential for the development of dorsal telencephalon (Yoshida, M., Suda, Y., Matsuo, I., Miyamoto, N., Takeda, N., Kuratani, S. and Aizawa, S. (1997) Development 124, 101-111). At the same time, Emx2 is expressed in the epithelial components of the developing urogenital system and, in Emx2 mutant mice, the kidneys, ureters, gonads and genital tracts were completely missing. Pax-2 and c-ret expressions in the Wolffian duct and WT-1 and GDNF expressions in the metanephric blastema were initially normal in the mutant. The ureteric bud grew and invaded the metanephric mesenchyme where Pax-2 expression was normally induced. Subsequently, however, Pax-2, c-ret and Lim1 expressions in the ureteric bud and GDNF expression in the mesenchyme were greatly reduced. Wnt-4 expression was never found in the mesenchyme. The tip of the ureteric bud never dilated and branching of the bud did not occur. Neither pretubular cell aggregates nor epithelialization were found in the mesenchyme. Instead the ureteric bud soon degenerated and apoptotic figures were prominent in mesenchymal cells. In explant culture, the mutant ureteric bud did not induce the epithelial transformation of the wild-type mesenchyme, and branching of the mutant ureteric bud was not induced by wild-type mesenchyme. In contrast, defects were not apparent in the mutant mesenchyme by co-culture with wild-type ureteric bud or spinal cord. These results suggest that, in metanephrogenesis, Emx2 is essential for the ureteric bud functions subsequent to Pax-2 induction in the metanephric mesenchyme. Degeneration of the Wolffian duct and mesonephric tubules was also abnormally accelerated without the formation of the Mullerian duct.


Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation.
The direct effects of IL-10 on the proliferation and lymphokine production of human peripheral blood T cells and CD4+ T cell clones representing the Th0, Th1-like, and Th2-like Th cell subsets were investigated in the absence of professional APC. IL-10 partially inhibited the proliferative responses of CD4+ human T cell clones induced by anti-CD2 or anti-CD3 mAb cross-linked on CD32 (Fc gamma RII)-transfected mouse L cells. Transfection of ICAM-1 or LFA-3 in CD32+ L cells resulted in enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD3 mAb, whereas transfection of B7 in CD32+ L cells enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD2 mAb. In addition, B7 expression on CD32+ L cells was required for activation of small resting T cells by anti-CD3 or anti-CD2 mAb. IL-10 inhibited the proliferation of T cell clones induced by anti-CD2 or anti-CD3 mAb on CD32+ L cells expressing these accessory molecules, indicating that interactions of LFA-3, ICAM-1, and B7 with their ligands on T cells did not overcome the inhibitory effects of IL-10. Inhibition of proliferation of T cell clones by IL-10 was in all instances completely neutralized by relatively low concentrations of IL-2, whereas IL-4 was ineffective. IL-10 did not affect the expression of the TCR/CD3 complex, CD2, LFA-1, CD28, or IL-2R alpha- or beta-chains, nor did it inhibit the induction of the latter two molecules on T cells after activation. Inhibition of proliferation was found to be the result of specific inhibition of IL-2 production by the responding T cell subsets, which occurred at the mRNA level. The production and mRNA levels of IL-4, IL-5, IFN-gamma, and granulocyte/macrophage-CSF were not affected by IL-10. Taken together, these results indicate that IL-10/IL-10R interaction on CD4+ T cell clones and peripheral blood T cells results in signaling pathways that specifically interfere with activation processes leading to IL-2 production. These direct inhibitory effects on IL-2 production by activated T cells may contribute to the general immunosuppressive activities of IL-10.


Clinical features in liver cirrhosis patients who have experienced ischemic stroke.
The actual incidence of ischemic stroke in patients with liver cirrhosis remains controversial. The aim of this study was to analyze the clinical features of patients with liver cirrhosis who have experienced ischemic stroke. A retrospective analysis was performed on the medical records of 23 ischemic stroke cases who were also diagnosed with liver cirrhosis, over a 10 year period from January 2001 to December 2010. Using the Child-Pugh classification system, Class B (39%) was the most common among the liver cirrhosis patients with ischemic stroke. There were six patients who presented with Class C (26%). Alcohol was analyzed as the main cause for liver cirrhosis in 14 patients (60.8%). Among the risk factors of ischemic stroke, nine of the 23 patients (39.1%) were diagnosed with obesity, and seven patients each (30.4%) were diagnosed with arrhythmia or smoking history. In total, only two patients (8.7%) had no association with any of the risk factors for ischemic stroke. Our results show that a comparatively high frequency of ischemic stroke occurs in patients with alcohol-induced liver cirrhosis and in patients with a less compromised liver function. In addition, it was found that most patients possessed at least one risk factor of ischemic stroke.


Salvage Strategy for Failed Spinal Fusion Surgery Using Lumbar Lateral Interbody Fusion technique: A Technical Note.
Failed spinal fusion surgery sometimes requires salvage surgery when symptomatic, especially with postsurgical decrease in intervertebral disc height followed by foraminal stenosis. For such cases, an anterior approach to lumbar lateral interbody fusion (LLIF) provides safe, direct access to the pathological disc space and a potential improvement in the fusion rate. One LLIF approach, oblique lateral interbody fusion (OLIF), targets the oblique lateral window of the intervertebral discs to achieve successful lateral interbody fusion. The current technical note describes spinal revision surgery using the OLIF procedure. The subjects were patients with leg pain and/or lower back pain derived from decreased intervertebral height followed by foraminal stenosis due to failed spinal fusion surgery. These patients underwent additional OLIF surgery and posterior fusion with no additional posterior direct decompression. Their outcomes were evaluated using the Japanese Orthopaedic Association (JOA) scores at baseline and final follow-up. Bony union was also evaluated using computed tomography images at final follow-up. Six subjects were evaluated, with two representative cases described in detail. Four patients had an adjacent segment disorder, and the other two patients had pseudarthrosis due to postoperative infection. The mean JOA score improved from 5.7 ± 5.4 to 21.2 ± 2.3, with a mean recovery rate of 65.0%. All cases showed intervertebral bony union. We introduced a salvage strategy for failed posterior spine fusion surgery cases using the OLIF procedure. Patients effectively achieved recovered intervertebral and foraminal height with no additional posterior direct decompression.


Screening for peripheral vascular disease in patients with type 2 diabetes in Malta in a primary care setting.
Peripheral vascular disease (PVD) is strongly associated with type 2 diabetes. PVD assessment and diagnosis are often neglected in primary care office visits, and ankle/brachial pressure index (ABPI) examinations are seldom performed for PVD detection. The purpose of this study was to evaluate the occurrence of PVD in a primary care setting using ABPI in patients with type 2 diabetes in Malta. A retrospective study was conducted on a cohort of 243 patients with type 2 diabetes to address various issues. As part of this large study, data from ABPI measurements collected using a portable hand-held Doppler with ankle pressures of <0.8 suggestive of PVD were extracted. Twenty-six per cent of the sample had to be referred for further vascular assessment following this screening programme due to their critical vascular status. Furthermore, at the time of examination, approximately 7% of the patients had an ABPI of less than 0.8 in both left and right extremities. A significant proportion of Maltese patients with type 2 diabetes who visit primary care present with vascular insufficiency. The use of ABPI should be considered as an added measurement in order to facilitate early detection and treatment and reduce the burden of PVD in this high-risk population.


Elder abuse and self-neglect: "I don't care anything about going to the doctor, to be honest...".
Elder mistreatment encompasses a range of behaviors including emotional, financial, physical, and sexual abuse, neglect by other individuals, and self-neglect. This article discusses the range of elder mistreatment in community-living older adults, associated factors, and consequences. Although self-neglect is not considered a type of abuse in many research definitions, it is the most commonly reported form of elder mistreatment and is associated with increased morbidity and mortality. The case on which this article is based describes a 70-year-old woman who neglects herself and dies despite multiple contacts with the medical community. Despite significant gaps in research, enough is known to guide clinical practice. This article presents the practical approaches a health care professional can take when a reasonable suspicion of elder mistreatment arises. Public health and interdisciplinary team approaches are needed to manage what is becoming an increasing problem as the number of older adults around the world increases.


Randomized trials of housing interventions to prevent malaria and Aedes-transmitted diseases: A systematic review and meta-analysis.
Mosquito-borne diseases remain a significant public health problem in tropical regions. Housing improvements such as screening of doors and windows may be effective in reducing disease transmission, but the impact remains unclear. To examine whether housing interventions were effective in reducing mosquito densities in homes and the impact on the incidence of mosquito-borne diseases. In this systematic review and meta-analysis, we searched 16 online databases, including NIH PubMed, CINAHL Complete, LILACS, Ovid MEDLINE, and Cochrane Central Register of Controlled Trials for randomized trials published from database inception to June 30, 2020. The primary outcome was the incidence of any mosquito-borne diseases. Secondary outcomes encompassed entomological indicators of the disease transmission. I2 values were used to explore heterogeneity between studies. A random-effects meta-analysis was used to assess the primary and secondary outcomes, with sub-group analyses for type of interventions on home environment, study settings (rural, urban, or mixed), and overall house type (traditional or modern housing). The literature search yielded 4,869 articles. After screening, 18 studies were included in the qualitative review, of which nine were included in the meta-analysis. The studies enrolled 7,200 households in Africa and South America, reporting on malaria or dengue only. The type of home environmental interventions included modification to ceilings and ribbons to close eaves, screening doors and windows with nets, insecticide-treated wall linings in homes, nettings over gables and eaves openings, mosquito trapping systems, metal-roofed houses with mosquito screening, gable windows and closed eaves, and prototype houses using southeast Asian designs. Pooled analysis depicted a lower risk of mosquito-borne diseases in the housing intervention group (OR = 0.68; 95% CI = 0.48 to 0.95; P = 0.03). Subgroup analysis depicted housing intervention reduced the risk of malaria in all settings (OR = 0.63; 95% CI = 0.39 to 1.01; P = 0.05). In urban environment, housing intervention was found to decrease the risk of both malaria and dengue infections (OR = 0.52; 95% CI = 0.27 to 0.99; P = 0.05).Meta-analysis of pooled odds ratio showed a significant benefit of improved housing in reducing indoor vector densities of both Aedes and Anopheles (OR = 0.35; 95% CI = 0.23 to 0.54; P<0.001). Housing intervention could reduce transmission of malaria and dengue among people living in the homes. Future research should evaluate the protective effect of specific house features and housing improvements associated with urban development.


An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet.
Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by a rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for treatment of various cholinergic deficiencies, including Alzheimer's disease and myasthenia gravis. In a previous high throughput screening campaign, we identified the dye crystal violet (CV) as an inhibitor of AChE. Herein, we show that CV displays a significant cooperativity for binding to AChE, and the molecular basis for this observation has been investigated by X-ray crystallography. Two monomers of CV bind to residues at the entrance of the active site gorge of the enzyme. Notably, the two CV molecules have extensive intermolecular contacts with each other and with AChE. Computational analyses show that the observed CV dimer is not stable in solution, suggesting the sequential binding of two monomers. Guided by the structural analysis, we designed a set of single site substitutions, and investigated their effect on the binding of CV. Only moderate effects on the binding and the cooperativity were observed, suggesting a robustness in the interaction between CV and AChE. Taken together, we propose that the dimeric cooperative binding is due to a rare combination of chemical and structural properties of both CV and the AChE molecule itself.


Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer.
Mammalian target of rapamycin (mTOR) signaling is a central regulator of protein translation, cell growth, and metabolism. Alterations of the mTOR signaling pathway are common in cancer, making mTOR a promising therapeutic target. In clinical trials, rapamycin analogs have shown modest response rates for most cancer types, including breast cancer. Therefore, there is an urgent need to better understand the mechanism of action of rapamycin to improve patient selection and to monitor pathway inhibition. To identify novel pharmacodynamic markers of rapamycin activity, we carried out transcriptional profiling of total and polysome-associated RNA in three breast cancer cell lines representing different subtypes. In all three cell lines, we found that rapamycin significantly decreased polysome-associated mRNA for stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis. Activators of mTOR increased SCD1 protein expression, whereas rapamycin, LY294002, and BEZ235 decreased SCD1 protein expression. Rapamycin decreased total SCD1 RNA expression without inducing a significant decline in its relative polysomal recruitment (polysome/total ratio). Rapamycin did not alter SCD1 mRNA stability. Instead, rapamycin inhibited SCD1 promoter activity and decreased expression of mature transcription factor sterol regulatory element binding protein 1 (SREBP1). Eukaryotic initiation factor 4E (eIF4E) small interfering RNA (siRNA) decreased both SCD1 and SREBP1 expression, suggesting that SCD1 may be regulated through the mTOR/eIF4E-binding protein 1 axis. Furthermore, SCD1 siRNA knockdown inhibited breast cancer cell growth, whereas overexpression increased growth. Taken together these findings show that rapamycin decreases SCD1 expression, establishing an important link between cell signaling and cancer cell fatty acid synthesis and growth.


Clinical applications of cardiopulmonary interactions.
The hemodynamic consequences of both spontaneous and positive-pressure ventilation may be profound and may have opposite effects on cardiovascular stability in differing patient populations. Thus, no firm rules apply as to the specific response that will be seen in all patients and under all conditions. Some generalities, however, are probably reasonable. In patients with markedly increased work of breathing, hypervolemia, or impaired LV pump function, the institution of mechanical ventilatory support can be lifesaving because of its ability to support the cardiovascular system, independent of any beneficial effects that mechanical ventilation may have on gas exchange. In patients with decreased pulmonary elastic recoil, increased pulmonary vascular resistance, hypovolemia, or airflow obstruction, the institution of mechanical ventilatory support may induce cardiovascular instability, which, if not corrected, can lead to total cardiovascular collapse. Similarly, withdrawal of ventilatory support invariably increases intrathoracic blood volume and LV afterload and can be thought of as a type of cardiovascular stress test. Patients who pass this test easily can usually be successfully weaned from mechanical ventilatory support, whereas those who fail often are not ready to be weaned. Some patients who fail weaning trials do so because of the cardiovascular effects of spontaneous ventilation, not because the work of breathing is too great. Identification of such patients early on may improve their treatment by directing supportive therapies toward cardiovascular rather than ventilatory endpoints. However, in many situations, it will be difficult to single out a primary process determining cardiovascular instability, because multiple factors are compounded to create the observed situation and the patient's response to initiation of ventilatory support or weaning. Thus, the clinician is left with a series of therapeutic options, which if depending on the patient's response, suggest specific origins of the ventilatory and cardiovascular dysfunction. In that regard, the initiation and withdrawal of ventilatory support can be seen as a ventilatory probe into the determinants of cardiovascular homeostasis in the ventilatory-dependent patient.


International Clinical Protocol on Vestibular Disorders (Dizziness).
26-28 May at 43 Congress of Neurootological and Equilibriometric Society (Budapest, Hungary) International Clinical Protocol on Vestibular Disorders (Dizziness) being discussed and accepted as Consensus Document. Cochrane reports estimates that dizziness has prevalence of 22.9% in the last 12 months and an incidence of 3.1%. Only 1.8% of adults consulted a physician in the last 12 months. Cochrane reviews suggest that the evidence base for dizziness evaluation is weak, thus necessitates the creation of evidence-based document. Protocol is based at the new concept of vestibular system, which involves the vestibular peripheral sensors, space orientation tetrad, vestibular presentations in the brain cortex and vestibular effectory projections in the brain. Labyrinth consists of sensors, for which six modalities are adequate: 1. acceleration, 2. gravitation, 3. low frequency whole-body vibration, 4. Infrasound, 5. magnetic impulse, 6. metabolic changes. Vestibular system from rhomboid fosse gets the inputs from visual, acoustic, somatosensory organs, integrating them and forming space perception and orientation. Interaction with space is realized through sensory, motor, vegetative and limbic projections. So, vestibular disturbances may manifest as paropsia, tinnitus, numbness. Vestibular evoked potentials (not VEMP) and craniocorpography have highest sensitivity (90% and more). As vestibular dysfunction has recurrent character patients need monitoring.


HIV risks and seroprevalence among Mexican American injection drug users in California.
Latinos in the United States are an ethnically diverse group disproportionately affected by HIV/AIDS. We describe HIV seroprevalence, HIV risk behaviors and utilization of health services among Mexican American injection drug users (IDUs) in California (n = 286) and compare them to White (n = 830) and African American (n = 314) IDUs. Study participants were recruited from syringe exchange programs (n = 24) in California. HIV seroprevalence among Mexican Americans (0.5%) was dramatically lower than Whites (5%) and African Americans (8%). Mexican Americans reported fewer sex-related risks than Whites and African Americans though injection-related risks remained high. Compared to Whites, Mexican Americans were more likely to participate in drug treatment during a 6 month period (AOR 1.5, 95% CI 1.1, 2.0) but less likely to receive any health care (AOR 0.6, 95% CI 0.5, 0.8). Exploring cultural and structural factors among Mexican American IDUs may offer new insights into how to maintain low rates of HIV seroprevalence and reduce barriers to health care utilization.